Is NHS p.Pro68= (c.204A>G) pathogenic?

NHS p.Pro68= (c.204A>G) is classified Benign/Likely benign in NHS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-28). Rare (popmax 0.191%, afr); Associated with Nance-Horan syndrome.

What condition is associated with NHS p.Pro68= (c.204A>G)?

NHS p.Pro68= (c.204A>G) is associated with Nance-Horan syndrome (ClinVar).

How common is NHS p.Pro68= (c.204A>G) in the general population?

NHS p.Pro68= (c.204A>G) is rare (popmax 0.191%, afr) (gnomAD).

NHS p.Pro68=

c.204A>G · rs775588477 · VCV714438

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.191%, afr)

Conditions

Nance-Horan syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.58	GERP -1.4, phastCons 0.97
Overall
CADD	6.684	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.191% African / African-American · 97/50,846 alleles

Filtering AF 0.16% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.149%

Overall 0.0102% 109/1,073,255 alleles · rare exomes 41/963,152 · genomes 68/110,103 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.191%	524
Middle Eastern	0.0357%	2,804
Admixed American	0.0133%	7,529
Remaining individualsnot grpmax-eligible	0.0121%	8,289
European (non-Finnish)	0.00024%	416,018

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NHS
Protein: p.Pro68=
Coding: c.204A>G
MANE Select: NM_001291867
dbSNP: rs775588477
Type: single nucleotide variant
Location: chrX:17375961 (GRCh38)
Structure: AlphaFold pLDDT 43.65
Residue 68: the 'wave homology domain (whd)' region; the 'disordered' region

Full NHS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Nance-Horan syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NHS p.Arg248Ter Pathogenic ★★ same condition
NHS p.Arg394Ter Pathogenic ★★ same condition
NHS p.Arg900Ter Pathogenic ★★ same condition
NHS p.Gln411Ter Pathogenic ★★ same condition
NHS p.Gln80Ter Pathogenic/Likely pathogenic ★★ same condition
NHS p.Ala564Val Uncertain significance ★★ same condition
NHS p.Ala745Val Uncertain significance ★★ same condition
NHS p.Arg162Cys Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/nhs-p-pro68 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown